Presbycusis, age-related hearing loss, is a major reason for social isolation and loss of quality of life in the elderly but we have neither a clear understanding of the mechanisms involved nor of strategies to prevent it. This program project brings together laboratories with long-standing interests in the biochemistry and molecular biology of stress pathways in the inner ear and a group of scientists with expertise in genetic studies in mice, for a series of interrelated studies of the fundamental cell biology and genetics of presbycusis. Project 1 (Antioxidant and homeostatic pathways) will test the hypothesis that antioxidant defenses and redox-sensitive signaling pathways decline with age rendering the inner ear more prone to cell injury and death. Project 2 (Stress pathways in the aging cochlea) extends this hypothesis to age-related changes in the classic stress response ("heat shock proteins"), by analyzing induced responses to stress during aging, and will generate new mouse models to examine this pathway in the cochlea. Project 3 (Genetic analysis of stress resistance and loss of hearing) focuses on the genetic controls and physiological regulators that modulate hearing loss in a population of genetically heterogeneous mice. Genotyping will provide a genomic map of loci modulating hearing acuity, its change over age, and its resistance to noise-induced damage. Specifically, the project will test the hypothesis that modulation of stress-resistance will modulate presbycusis. The projects will be supported by three cores. Core A (Administration) will coordinate reporting and evaluation activities and facilitate interactions among the projects. Core B (Physiology) will evaluate auditory function, and Core C (Otopathology/Histology) will assess morphological changes and provide histological assays. The three projects are taking distinct but complementary approaches to delineate the molecular and genetic basis of age-related hearing loss. The results will answer questions on the relationships among two well-characterized stress pathways in the aging cochlea, and identify new genetic loci associated with age-related hearing loss.